Cortical and subcortical computed tomographic study in schizophrenia

Vol. 22, No. 2, pp. 99-105, 1988 Printed in GreatBritain.

0022-3956/88$3.00+00 Pergamon Press pie

J. psychiat. Res.,

CORTICAL AND SUBCORTICAL COMPUTED TOMOGRAPHIC S T U D Y IN S C H I Z O P H R E N I A ALESSANDRO Rossi*, PAOLO STRATTA*, STEFANO DE CATALDO*, VITTORIO DI MICHELE*, GIUSEPPE ORFANELLI~, ANTONIO SERIO~, CONCETTA PETRUZZI~ a n d MASSIMO CASACCHIA*

*Chair of Clinical Psychiatry, S.M. CoUemaggioHospital, L'Aquila, Italy and t Nursing Home "Villa Serena", Cittfi S. Angelo (Pescara), Italy

(Received 10 July 1987; revised 14 October 1987) Summary--Thirty-sixchronic schizophrenicsand 24 controls, all males, wereevaluatedby computed tomography (CT) scans. The lateral, third and fourth ventricles, the Sylvianfissure and the largest sulcus from each lobe were measured. In the schizophrenicpatients there was a significant increase in third ventricle, ventricular brain ratio (VBR) and cortical measures. The possible implications of these findings in the aetiopathology of schizophrenia are discussed. INTRODUCTION SEWRAL lines of evidence, generated by numerous computed tomography (CT) studies have suggested the presence of morphological abnormalities in the brain of some schizophrenic patients. The most c o m m o n l y reported finding is lateral ventricular enlargement (LVE) (JOHNSTONE et al., 1976; WEINBERGER et al., 1979a). The origin o f cerebral ventricular enlargement in chronic schizophrenia (variously reported as 6-53 percent) remains unknown, but there seems to be no relationship with age (GOLDEN et al., 1980) and drug treatment (WEINBERGER et al., 1979a). An association between neuropsychological impairment and brain abnormalities has also been reported (Dom~mLLY et al., 1980; GOLDEN et al., 1980). Other studies reported cerebellar atrophy (HEATH et al., 1982; LIPPU_~NNet al., 1982) and third-ventricular enlargement (TANAKA et al., 1981). Cortical abnormalities have also been reported (WEINBEI~GER et al., 1979a). Other investigators, however, have found no morphological abnormalities in schizophrenics (TRIMBLEand KINGSLEY, 1978; BENES et al., 1982; JERmGAN et al., 1982). Enlargement of the ventricular system has been considered to be suggestive of subcortical atrophy or to be a passive process following cortical atrophy. Recently, the issue has been addressed that the core pathology of a sub-group of chronic schizophrenic patients m a y lie in the third ventricle-diencephalic region (DEWAN et al., 1983, 1986; PANDURANGI et al., 1984). In spite o f several investigations that have separately shown enlargement o f each o f the different parts o f the ventricular system in schizophrenia, only a few reports have studied the entire ventricular system in the same group o f patients, reporting results as continuous variables (DEwAN et al., 1986). The aim o f the present study was to examine the entire Address correspondenceto: Dr Alessandro Rossi, Clinica Psichiatrica deU'Universita'de L'Aquila, c/o Ospedale S.Maria di Collemaggio, 67100 L'Aquila, Italy. Tel. 0862-78812. 99

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ventricular system and cerebral cortex in order to elucidate possible structural abnormalities in schizophrenic patients. Because of the influence of sex on schizophrenia and for the purpose of better control and homogeneity of clinical samples, the study was limited to men. SUBJECTS AND METHODS We obtained informed consent to a CT scan from 36 male patients diagnosed as chronic schizophrenics by Diagnostic and Statistical Manual (DSM-III) criteria. DSM-III subtypes were: paranoid 8 (22.22070) and non-paranoid 28 (77.78o70). Their mean age was 42.69 4-10.3 (mean4-SD) yr (range 23-59) and the mean duration of illness was 19.08 yr (7.85 SD). All of our patients received neuroleptics; none have been chronically hospitalized. None of them had a history of alcoholism or drug abuse. No patients had evidence of neurological disorder. The controls were 24 prospectively selected males (mean age ± SD, 35.37 4-13.99 yr, range 17-59) who had a history of headache (17 cases) or recent minor-vehicle accident but no positive neurological findings (7 cases). The CT scan was performed as a screening procedure to detect structural abnormalities in patients with a history o f non-specific headaches or minor head trauma. None of the control CT scans disclosed any abnormalities such as intracranial mass, infarct, haemorrhage, or hydrocephalus. These controls had no documented history of drug and alcohol abuse or physical illness. COMPUTED TOMOGRAPHIC BRAIN SCAN CT scans (all without contrast) were performed on all subjects, with a 320 x 320 matrix head scanner (CT GE 9000 II). Each subject had 12 cuts, 10mm thick, made at 15 ° to the orbitomeatal line; slice 1 was the more caudal, slice 12 the more apical. The films were coded, and measurements of cerebral ventricular size were made by a research technician who was unaware of the diagnosis, using computer-assisted planimetry on the CT video console. Test-retest reliability (intraclass correlation coefficient) was at the level of 96°7o. The section that passed through the body of the lateral ventricles and showed maximum ventricular area was used for each patients and control subject. This was usually slice 8 or 9. The area of the ventricles and the area of the brain at that level were measured, and cerebral ventricular size was expressed as the ventricle-brain ratio (VBR). Linear measurements considered in this paper are: (i) maximum width of the third ventricle (usually slice 6 or 7); (ii) maximum width o f the fourth ventricle (slice 4); (iii) maximum widths of the Sylvian fissures (slice 6 or 7); (iv) maximum width of the largest cortical sulcus in each lobe of both hemispheres, measured in the slice where it was best visible. If a structure was not measureable, it was not considered for statistical purposes. Linear measurements were expressed in millimeters (mm). STATISTICAL ANALYSIS Because of the significant age difference between the two groups (two-tailed t-test, P = 0 . 0 2 ) , factorial analysis o f variance (ANOVA) for unequal cell frequencies was performed by three age decades × group-condition (i.e. patients vs controls) (Walonick DS J 083, Statpac--Statistical Analysis package), VBR, third and fourth ventricular sizes, fissure

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and sulci measurements were the dependent variables. The relationship between variables was studied by Pearson's product-moment correlations. RESULTS

A two-way ANOVA to study the impact of the effect of group and age decade on VBR revealed significant differences for group and age with no significant group × age interaction. The same analysis conducted on third ventricle size revealed a significant group effect but no significant age and group × age effect. A two-way ANOVA with respect to the fourth ventricles showed no significant group-, age- and group × age effect (Table 1). In the patient group, the sulcal measurements were significantly larger for the right frontal sulcus, left parietal sulcus and left Sylvian fissure (Table 2). No significant differences were seen for age factor and g r o u p × age interaction. There was a consistent difference between schizophrenics and controls in the pattern of correlations among CT measurements: in the patient group, highly statistically significant correlations were found between VBR, on the one hand, and third and fourth ventricular measurements on the other ( r = 0.58; P < 0.001 and r = 0.42; P < 0.01), while in the control group the same coefficients did not reach the statistically significant level of 0.05 (r = 0.09 and r = 0.26). In the control group, only a correlation between third and fourth ventricle showed the same trend as in the patient group (r= 0.41 and 0.44 respectively). In a group of 31 patients, from whom ventricular, parietal, frontal and Sylvian measurements were available, the following significant correlations, at P < 0.05 level, were found: VBR vs third ventricle width (r = 0.73), VBR vs age (r = 0.5); age vs third ventricle width (r= 0.43); left Sylvian fissure vs third ventricle width (r = 0.54). In the whole group of 36 patients, the correlation coefficient between VBR and age was r = 0 . 3 6 while in the control group it was r = 0 . 3 5 (for both, P < 0.05). No significant correlation was seen between linear and area measurements and duration of illness.

DISCUSSION

By making quantitative measurements and controlled comparisons of cerebral structures on CT scans, it is possible to demonstrate subtle abnormalities in brain morphology that might otherwise be overlooked. Cortical atrophy is considered a difficult diagnosis to make with certainty from a CT image, particularly if the findings are not dramatic. Several published studies have, in fact, attempted to define a threshold for abnormal cortical sulcal width (HucKMAN et al., 1975; ROBERTSet al., 1976). In the present study, we have reported a statistically significant frontal right and parietal left sulci dilatation and a Sylvian left fissure enlargement in the cerebral cortex o f schizophrenics compared with controls. The character o f our control group may also affect the findings. Ideally, normal healthy volunteers should be used (OwEN and Lr~wis, 1986), but in our study, as in some others investigations (Tanaka et al., 1981; BE~,rESet al., 1982; P.~a,muga_nGi et al., 1984), the control group consisted o f neurological patients. The choice of these patients satisfies a number o f ethical issues but may introduce bias and favour a higher proportion of patients with abnormal scans in the control group, minimizing the " t r u e " between-group differences. Other studies have previously shown cortical atrophy in schizophrenia (WEmBEROER et

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TABLE 2. Sr.rLCALMEASUREMENTSOBTAINED BY CT SCAN IN CHRONIC SCItIZOPHRENICSAND CONTROLS Age

Controls

Schizophrenics Right

41 50

40 50 --

-41 51

40 50 --

-41 51

40 50 --

-

-

-

-

41 51

40 51 --

Controls

Schizophrenics

Sylvian fissure (mm)

Left 4.21 ± 1.35(9) 4.81 4-1.49(15) 4.02 ± 1.46(5) 5.49 4-1.70(11) 4.604-0.90(4) 6.024-3.21 (8) 0o) F 1,46=4.203; P = 0 . 0 4 Frontal sulcus (mm) Right Left 1.87±0.29(4) 2.76±0.08(15) 2.07 ±0A5(7) 2.40-u 0.91(14) 2.354-0.54(6) 2.784-0.58(12) 3.074-0.96(4) 3.14-u 1.40(11) 2.204-0.36(5) 2.974-1.22 (8) 2.324-0.06(5) 3.31 ± 1.05 (9) (b) F 1,44=8.39; P = 0 . 0 0 6 Parietal sulcus (mm) Right Left 2.074-0.41(10) 2.744-0.56(15) 1.954-0.57(10) 3.034-0.71(15) 2.56 -u 0.42(5) 2.90 4- 0.75(12) 2.38 4- 0.39 (5) 3.01 4- 0.49(11) 2.604-0.51 (3) 2.604-0.76 (9) 2.64-u0.39 (5) 2.784-0.82 (9) (b) F 1,49=11.52; P = 0 . 0 0 2 Occipital sulcus (mm) Right Left 1.56 4- 0.36(6) 2.64 ± 0.66(5) 2.15 4- 0.54(10) 2.08 4- 0.39(6) 2.50-u 0.98(2) 2.464-0.91(5) 2.62±0.45 (4) 1.80±0.48(6) 1.56±0.40(3) 2.07±0.91(7) 2.204-0.36 (3) 2.41 4-0.44(7) 4.10-u 1.05(8) 5.96 4- 3.53(5) 4.524-1.12(4)

4.02 4- 1.42(14) 5.27 ± 1.43(10) 6.80±2.65 (8)

All values are reported as mean-~ SD. In parentheses, measurable cases. Only significant difference at P < 0.05 level are reported: (a)= age factor; (b)= group factor.

al., 1979b; DEWAN et al., 1986) but others have not confirmed such an observation (JERNrGAN et aL, 1982; OKASrIA and MADKOtrR, 1982).

We report here that our schizophrenics show a statistically larger VBR, cortical atrophy and a highly signifcantly larger third ventricular width. DEWAN et al. (1983, 1986) and PAgDtrRAN6I et aL (1984) reported an enlargement of the third and fourth ventricle and of the Sylvian fissure as well. In their sample, VBR and cerebral sulci did not differ from controls. The authors concluded that there might be a sub-group of chronic schizophrenics whose core pathology is in the third ventricle-diencepalic region. Other studies had reported a significant increase in third ventricular size (TANAKA et al., 1981; OKASnA and MADKOUR, 1982; BORONOWet al., 1985), associated with lateral ventricular enlargement (NYBACKet al., 1982). These studies, reporting "central atrophy" in schizophrenia, have found partial support in a recent post-mortem report by STEWNS (1982) who found increased fibrillary gliosis that principally affected the periventricular structures of the diencephalon and the periaqueductal region of the mesencephalon, suggesting previous or low-grade inflammation. The author hypothesized that' 'the finding of subependymal gliosis in the diencephalon and hypothalamus or of pallid neuron d r o p o u t . . , is consistent with the evidence of moderate enlargement of the third and lateral ventricles reported i n . . . schizophrenia". Only a few studies have examined the relationship between VBR and cortical atrophy (WEmBERGER et al., 1979b, NAS~a~LLAnet al., 1982). The prevailing view is to consider atrophy in schizophrenia in terms of components (i.e. cerebral ventricle, cortical sulci) which are not considered to be interrelated (WEmBERGERet aL, 1979b). Our findings challenge

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this hypothesis because we report significant correlations between some of the abnormal measurements (i.e. VBR vs third ventricle width, left Sylvian fissure vs third ventricle width) with a possible relationship between indices of cerebral atrophy suggesting diffuse mild cerebral atrophy. We show that when several measurements are made on the same CT scan and in the same patient group, statistically significant relationships emerge. Nevertheless, the possibility that the finding was a chance occurrence due to the large number of relationships investigated must be considered. This finding underlines the need for a global assessment of the ventricular and cortical system in CT studies before jumping to the conclusion that several subgroups of patients with dissimilar abnormalities exist (i.e. those with third ventricle enlargement, those with cortical atrophy and those with lateral ventricle enlargement). The possibility of grouping schizophrenic patients on the basis of correlational analysis between CT measures should only be considered with caution. As pointed out by several authors, CT findings should be corroborated by concurrent clinical and biochemical evaluation (VANKAm~N et al., 1986) which may add further clues to our understanding of the phenomenon of "atrophy". Magnetic resonance imaging techniques, characterizing the physicochemical environment of brain tissue (Rossi et al., 1987) might also be used concurrently with the CT scan to clarify the significance of CT findings. REFERENCES BENES, F., SImDERLAm~,P., JONES,B. D., LEVY, M., CottoN, B. M. and Lm~sKI, J. F. (1982) Normal ventricles in young schizophrenics. Br. J. Psychiat. 141, 90-93. BORONOW,J., PICKAR,D., NINAN, P. T., RoY, A., HomaxR, D., LINNOILA,M. and STEVEN,P. (1985) Atrophy limited to the third ventricle in chronic schizophrenic patients. Archs gen. Psychiat. 42, 266-271. DEWAN, M. J., PANDURANGI,A. K., LEE, S. H., RA~Cm~'CORAN, T., LEVY, B., BOUCHER,M., YOZAWITZ,A. and MAJOR, L. (1983) Central brain morphology in chronic schizophrenic patients: a controlled study. BioL Psychiat. 18, 1133-1140. DEWAN, M. J., PANDURANGI,A. K., LEE, S. H., RAMACI-IANDRAN,T., LEVY, B., BOUCHER,i . , YORAWlTZ, A. and MAIOR, L. (1986) A comprehensive study of chronic schizophrenic patients. Actapsychiat. scand. 73, 152-160. DONNELLY,E. G., WEINBERGER,D. R., WALm~N, I. N. and WYATT,R. J. (1980) Cognitive impairment associated with morphological brain abnormalities on computed tomography in chronic schizophrenic patients. J. nerv. m e n t . Dis. 168, 305-308. GOLDEN, C. J., MOSES, J. A., ZELAZOWSKI,M. A., GRABER, B., ZATZ, L. M., HORVATH,T. B. and BERGER, P. A. (1980) Cerebral ventricular size and neuropsychological impairment in chronic schizophrenia. Archs gen. Psychiat. 37, 619-623. HEATH, R. G., FRANKLIN,D. E., WALKER,C. F. and KEATI~G,J. W. (1982) Cerebellar vermal atrophy in psychiatric patients: Biol Psyehiat. 17, 569-585. Hucrdr~N, M. S., Fox, J. and TOPEL, J. (1975) The validity of criteria for the evaluation of cerebral atrophy by computed tomography. Radiology 116, 85-87. JERNIGAN,T. L., ZATZ, L. M., MOSES,J. A. and BERGER,P. A. (1982) Computed tomography in schizophrenics and normal volunteers. I. Fluid volume. A r c h s gen. Psychiat. 39, 765-770. JOHNSTONE,E. C., CROW, T. J., FRITH, C. D., HUSBAND,J. and KI~EL, L. (1976) Cerebral ventricniar size and cognitive impairment in chronic schizophrenia. Lancet ii, 924-926. LIPP~NN, S., MA~SrlADI, M., BALDWIN,H., DRASlN, G., RICE, J. and A L ~ H , S. (1982) Cerebellar vermis dimensions on computerized tomographic scans of schizophrenic and bipolar patients. Am. J. Psychiat. 139, 667-8. NASRALLAIi,H. A., McCALLEY-WmTTERS,M. and JACOBY,C. G. (1982) Cortical atrophy in schizophrenia and mania. J. clin. Psychiat. 43, 439-441. NYBACK, S., WmSEL, F. A., BERC,GREN, B. M. and HINDMARSH,T. (1982) Computed tomography of the brain in patients with acute psychosis and in healthy volunteers. Acta psychiat, scand. 65, 403-13.

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Or~SHA, A. and I~/IADKOUR,O. (1982) Cortical and central atrophy in chronic schizophrenia. A controlled study, Acta psychiat, scand. 65, 29-34. OW~N, M. J. and LEwis, S. W. (1986) Lateral ventricular size in schizophrenia. Lancet il, 223-224. PA~OURA~GI,A. K., DEWAr, M. J., LEE, H. S., RAMACnA~DRAN,T., LEVY, B. F., BoucI-mg, M., YozAwrrz A. and MAJOR, L. (1984) The ventricnlar system in chrinic schizophrenic patients. A controlled computed tomography study. Br. J. Psychiat. 144, 172-176. ROBERTS, M. A., CAnto, F. I., GROSS~a~T,K. W. and STEVEN, J. L. (1976) Computerized tomography in the diagnosis of cerebral atrophy. J. NeuroL Neurosurg. Psychiat. 39, 309-915. RossI, A., STRATTA,P., CASACCHIA,M., GALLUCCI,M. and PASSARmLLO,R. (1987) Nuclear magnetic resonance imaging in schizophrenia: a preliminary study. In: Etiopathogenetic Hypothesis of Schizophrenia: the Impact of Epidemiological, Biochemical and Neuromorphological Studies (Edited by SACCn~TT~,E., CAZZULLO,C. L., INVERmZZI, G. and VrrA, A.). MTP, Lancaster 1987. STEVENS, J. E. (1982) Neuropathology of schizophrenia. Archs gen. Psychiat. 39, 1131-1139. TAr~A~A, Y., HAZAMA,H., KAWAnARA,R. and KOBAYSm,K. (1981) Computerized tomography of the brain in schizophrenic patients. A controlled study. Acta psychiat, scand. 63, 191-197. TR~BL~, M. and KINGSLEY,D. (1978) Cerebral ventricular size in chronic schizophrenia. Lancet i, 278-279. VA~ KAMM~N, D. P., VAN KAMM~N, W. B., MANN, L. S., SEPPALA,T. and LINNOILA,M. (1986) Dopamine metabolism in the cerebral spinal fluid of drug-free schizophrenic patients with and without cortical atrophy. Archs gen. Psychiat. 43, 978-983. W~INBER~ER, D. R., T O ~ Y , E. F., NEOPHYTrO~S,A. N. and WYATT,R. J. (1979a) Lateral cerebral ventricular enlargement in chronic schizophrenia. Archs gen. Psychiat. 36, 735-739. WEINSERGER, D. R., TORr,~Y, E. F., NEOPaYTmES, A. N. and WYATT, R. J. (1979b) Structural abnormalities in the cerebral cortex of chronic schizophrenic patients. Archs gen. Psychiat. 36, 935-939.